Skip to main content

Controlled Human Malaria Infection (CHMI) Studies: Over 100 Years of Experience with Parasite Injections

Part of the Methods in Molecular Biology book series (MIMB,volume 2013)


Human experimentation by deliberate infection with malarial parasites seems unethical yet has a long history in infectious disease research. After rigorous screening, volunteers are inoculated with Plasmodium sporozoites or blood stages and monitored under strict clinical supervision until they are treated with a licensed malaria drug and the infection is completely resolved. Historically, experimental Plasmodium challenge infections were applied to confirm that Anopheles mosquitoes were the malaria vector and to treat neurosyphilis in Treponema pallidum-infected patients. The lifesaving treatment with reliable parasite inoculation, monitoring, and drug cure was awarded with a Nobel Prize in 1927 and paved the way for human trials for clinical tests of candidate drugs and vaccines. Importantly, controlled human malaria infection (CHMI) studies are indispensable to bridge the major gap between phase I safety and phase II field trials. Here, we describe the biological basis, historical experiences, applications, and ethical considerations for CHMI studies. Acceleration of antimalarial drug and vaccine development remains a priority in medical research and critically depends on capacity building for CHMI studies.

Key words

  • Malaria
  • Plasmodium
  • Human trials
  • Clinical monitoring
  • Adverse effects
  • Sporozoite
  • Asexual blood stage
  • Vaccines
  • Drugs

This is a preview of subscription content, access via your institution.

Buying options

USD   49.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4939-9550-9_7
  • Chapter length: 11 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
USD   109.00
Price excludes VAT (USA)
  • ISBN: 978-1-4939-9550-9
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   149.99
Price excludes VAT (USA)
Hardcover Book
USD   219.99
Price excludes VAT (USA)

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more


  1. Sauerwein RW, Roestenberg M, Moorthy VS (2011) Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat Rev Immunol 11:57–64

    CAS  PubMed  Google Scholar 

  2. Payne RO, Griffin PM, McCarthy JS et al (2017) Plasmodium vivax controlled human malaria infection–progress and prospects. Trends Parasitol 33:141–150

    PubMed  PubMed Central  Google Scholar 

  3. Stanisic DI, McCarthy JS, Good MF (2018) Controlled human malaria infection: applications, advances and challenges. Infect Immun 86:e00479–e00417

    CAS  PubMed  Google Scholar 

  4. Grassi B, Bignami A, Bastianelli G (1899) Ulteriore ricerche sul ciclo dei parassiti malarici umani sul corpo del zanzarone. Atti Reale Accad Lincei 8:21–28

    Google Scholar 

  5. Manson P (1900) Experimental proof of the mosquito-malaria theory. Br Med J 2:949–951

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Clyde DF, Most H, McCarthy VC et al (1973) Immunization of man against sporozoite-induced falciparum malaria. Am J Med Sci 266:169–177

    CAS  Google Scholar 

  7. Trager W, Jensen JB (1976) Human malaria parasites in continuous culture. Science 193:673–675

    CAS  Google Scholar 

  8. Roestenberg M, Bijker EM, Sim BK et al (2013) Controlled human malaria infections by intradermal injection of cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg 88:5–13

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Teirlinck AC, Roestenberg M, van de Vegte-Bolmer M et al (2013) NF135.C10: a new Plasmodium falciparum clone for controlled human malaria infections. J Infect Dis 207:656–660

    CAS  PubMed  Google Scholar 

  10. Walk J, Reuling IJ, Behet MC et al (2017) Modest heterologous protection after Plasmodium falciparum sporozoite immunization: a double-blind randomized controlled clinical trial. BMC Med 15:168

    PubMed  PubMed Central  Google Scholar 

  11. Hermsen CC, Telgt DS, Linders EH et al (2001) Detection of Plasmodium falciparum malaria parasites in vivo by real-time quantitative PCR. Mol Biochem Parasitol 118:247–251

    CAS  PubMed  Google Scholar 

  12. Roestenberg M, McCall M, Hopman J et al (2009) Protection against malaria challenge by sporozoite inoculation. N Engl J Med 361:468–477

    CAS  PubMed  Google Scholar 

  13. Coffeng LE, Hermsen CC, Sauerwein RW et al (2017) The power of malaria vaccine trials using controlled human malaria infection. PLoS Comput Biol 13:e1005255

    PubMed  PubMed Central  Google Scholar 

  14. Mordmüller B, Supan C, Sim KL et al (2015) Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres. Malar J 14:117

    PubMed  PubMed Central  Google Scholar 

  15. Lell B, Mordmüller B, Dejon Agobe JC et al (2018) Impact of sickle cell trait and naturally acquired immunity on uncomplicated malaria after controlled human malaria infection in adults in Gabon. Am J Trop Med Hyg 98:508–515

    CAS  PubMed  Google Scholar 

  16. Engwerda CR, Minigo G, Amante FH et al (2012) Experimentally induced blood stage malaria infection as a tool for clinical research. Trends Parasitol 28:515–521

    PubMed  Google Scholar 

  17. Bejon P, Williams TN, Nyundo C et al (2014) A micro-epidemiological analysis of febrile malaria in Coastal Kenya showing hotspots within hotspots. elife 3:e02130s

    Google Scholar 

Download references


K.M. is supported partly by the Alliance Berlin Canberra “Crossing Boundaries: Molecular Interactions in Malaria”, which is co-funded by a grant from the Deutsche Forschungsgemeinschaft (DFG) for the International Research Training Group (IRTG) 2290 and the Australian National University. S.B. is investigator at the German Centre for Infection Research (DZIF) and a recipient of a DFG grant to study parasite-vector interactions. We acknowledge the many important contributions that have been made over the past 100 years in the field. For the purpose of this chapter, we selected a few seminal references and had to omit many equally important contributions. We apologize to our colleagues afflicted by this choice.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Kai Matuschewski or Steffen Borrmann .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Verify currency and authenticity via CrossMark

Cite this protocol

Matuschewski, K., Borrmann, S. (2019). Controlled Human Malaria Infection (CHMI) Studies: Over 100 Years of Experience with Parasite Injections. In: Ariey, F., Gay, F., Ménard, R. (eds) Malaria Control and Elimination. Methods in Molecular Biology, vol 2013. Humana, New York, NY.

Download citation

  • DOI:

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9549-3

  • Online ISBN: 978-1-4939-9550-9

  • eBook Packages: Springer Protocols